Compressive Stress Enhances Invasive Phenotype of Cancer Cells via Piezo1 Activation

Uncontrolled growth in solid tumor generates compressive stress that drives cancer cells into invasive phenotypes, but little is known about how such stress affects the invasion and matrix degradation of cancer cells and the underlying mechanisms. Here we show that compressive stress enhanced invasion, matrix degradation, and invadopodia formation of breast cancer cells. We further identified Piezo1 channels as the putative mechanosensitive cellular components that transmit the compression to induce calcium influx, which in turn triggers activation of RhoA, Src, FAK, and ERK signaling, as well as MMP-9 expression. Interestingly, for the first time we observed invadopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell9s ventral side. Furthermore, we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo1 and caveolae were often colocalized, and reduction of Cav-1 expression or disruption of caveolae with methyl-beta-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress. Taken together, our data indicate that mechanical compressive stress activates Piezo1 channels to mediate enhanced cancer cell invasion and matrix degradation that may be a critical mechanotransduction pathway during, and potentially a novel therapeutic target for, breast cancer metastasis.